Approximately 20% of general population in the United States has fatty liver, which is associated with obesity, alcohol drinking, metabolic disease, medications, type 2 diabetes. The prevalence of fatty liver is expected to further increase at alarming rate due to the overall increase in the prevalence of obesity. For example, currently, about 22.5% of U.S. citizens are obese, and this prevalence is expected to reach 40% by the year 2025. Fatty liver is a significant risk factor for serious liver disease. However, the molecular mechanism underlying fatty liver development is not clear and there is no pharmacologic agent that is known to prevent or reverse fatty liver disease. Mitochondrial dysfunction caused by oxidative stress is an early event that plays an important role in the pathogenesis of alcohol-induced apoptosis and steatosis. We hypothesize that the protective role of IL-6 in alcohol-induced liver injury is mediated via suppression of alcohol-induced oxidative stress and mitochondrial dysfunction. To test this hypothesis, we examined the effects of IL-6 on alcohol-induced oxidative stress, mitochondrial injury, and energy depletion in the liver of IL-6 (-/-) mice and hepatocytes from alcohol-fed rats or genetically obese Zucker rats. Alcohol consumption leads to stronger induction of malondialdehyde (MDA) in IL-6 (-/-) mice compared to wild-type control mice, which can be corrected by administration of IL-6. In vitro, IL-6 treatment prevents alcohol-mediated induction of reactive oxygen species (ROS), MDA, and mitochondrial permeability transition (MPT), and alcohol-mediated depletion of adenosine triphosphate (ATP) in hepatocytes from alcohol-fed rats or steatotic Zucker rats. Administration of IL-6 in vivo also reverses alcohol-induced steatosis, MDA, and ATP depletion. Finally, IL-6 treatment markedly induces metallothionein protein and mRNA expression, but not superoxide dismutase and glutathione peroxidase in cultured hepatocytes. In conclusion, IL-6 protects against alcohol-induced oxidative stress and mitochondrial dysfunction in hepatocytes via, at least in part, induction of metallothionein protein expression, which may account for the protective role of IL-6 in alcoholic liver disease.